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Key information relevant to the recruitment process for the
overall study, such as dates of the recruitment period and locations

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Pre-Assignment Details

Significant events and approaches for the overall study
following participant enrollment, but prior to group assignment

The study was comprised of Parts A, B, and D, which constitute the Phase I part of the study, and Part C, which constitutes the randomized Phase II part of the study. Participants did not enroll in all parts of the study sequentially. Each part of the study was comprised of a separate population of participants.

Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.

Part B: Dabrafenib 150 mg + Trametinib 1 mg

Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.

Part B: Dabrafenib 150 mg + Trametinib 1.5 mg

Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.

Part B: Dabrafenib 150 mg + Trametinib 2 mg

Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.

Participants who received dabrafenib 150 mg capsules BID alone in the Randomized Phase were given the opportunity to receive combination dosing of dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD upon disease progression with approval of the GlaxoSmithKline (GSK) Medical Monitor.

Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg

Participants received dabrafenib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.

Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg

Participants received dabrefinib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 75 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available pharmacokinetic (PK), safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on dose-limiting toxicities (DLTs) occurring during the first 3 weeks of treatment.

Part B: Dabrafenib 150 mg + Trametinib 1 mg

Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors and participants who had salivary ductal cancer received dabrafenib 150 mg gelatin capsules BID and trametinib 1 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.

Part B: Dabrafenib 150 mg + Trametinib 1.5 mg

Melanoma BRAF-positive participants who did not receive prior treatment with BRAF inhibitors received dabrafenib 150 mg gelatin capsules BID and trametinib 1.5 mg tablets QD as continuous daily dosing. Dose escalation decisions were made based on all available PK, safety, and other data from the first 4 evaluable participants, and additional participants were enrolled based on DLTs occurring during the first 3 weeks of treatment.

Part B: Dabrafenib 150 mg + Trametinib 2 mg

Melanoma BRAF-positive participants who received prior treatment with BRAF inhibitors and participants who had colorectal cancer and BRAFi naïve melanoma received dabrafenib 150 mg gelatin capsules BID and trametinib 2 mg tablets QD as continuous daily dosing. Dose escalation did not proceed beyond these doses of dabrafenib and trametinib.

Participants received dabrafenib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.

Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg

Participants received dabrafenib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.

Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part B [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks) ]

Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part B [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks) ]

Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part B [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks) ]

Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator in Part C (Randomized) [ Time Frame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 47 weeks) ]

Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response Assessed by Blinded Independent Central Review (BICR) in Part C (Randomized) [ Time Frame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 36 weeks) ]

Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator in Part C (Crossover) [ Time Frame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 15 weeks) ]

Duration of Response as Assessed by the Investigator and Blinded Independent Central Review (BICR) in Part C (Randomized) [ Time Frame: First documented evidence of PR or CR until the date of the first documented sign of disease progression or the date of death due to any cause (up to approximately 17 months) ]

Progression-free Survival (PFS) as Assessed by the Investigator in Part C (Randomized) [ Time Frame: From the first dose of study medication to the earliest date of disease progression (PD) or death due to any cause (up to approximately 17 months) ]

Progression-free Survival (PFS) as Assessed by the Blinded Independent Central Review (BICR) in Part C (Randomized) [ Time Frame: From the first dose of study medication to the earliest date of disease progression (PD) or death due to any cause (up to approximately 17 months) ]

Progression-free Survival (PFS) as Assessed by the Investigator in Part C (Crossover) [ Time Frame: From the first dose of study medication to the earliest date of disease progression (PD) or death due to any cause (up to approximately 9 months) ]

Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part C (Randomized) [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 75 weeks) ]

Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part C (Randomized) [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 75 weeks) ]

Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part C (Randomized) [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 75 weeks) ]

Number of Participants With the Indicated Worst-case Grade (G) Change From Baseline in the Indicated Clinical Chemistry Parameters in Part D [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks) ]

Number of Participants With the Indicated Worst-case Grade Change From Baseline in the Indicated Hematology Parameters in Part D [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks) ]

Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure in Part D [ Time Frame: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks) ]

Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau) and Maximum Plasma Concentration (Cmax) of Dabrafenib and Its Metabolite in Combination With Trametinib in Part B [ Time Frame: Day 15 and Day 21 ]

Number of Participants With BRAFi-naïve Mutant Metastatic Melanoma With the Best Overall Response as Assessed by Investigator in Part B [ Time Frame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to 103 weeks) ]

Duration of Response as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma in Part B [ Time Frame: First documented evidence of PR or CR until the earlier of date of disease progression or date of death due to any cause (up to approximately 22 months) ]

Progression-free Survival (PFS) as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma in Part B [ Time Frame: From the date of first dose to the earliest date of disease progression (PD) or death due to any cause (up to approximately 22 months) ]

The tmax of trametinib after single and repeat dose in combination with dabrafenib (DAB) was observed at Day 1 and Day 21. Blood samples for PK analysis of dabrafenib were obtained at pre-dose Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours (Day 1 only) post-dose administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin.Participants receiving DAB 75 mg to DAB 75 mg + Trametinib 2 mg and those receiving DAB 150 mg to DAB 150 mg + Trametinib 2 mg did not receive Trametinib until Day 29; therefore, tmax was not analyzed in these participants at Days 1 and 21.

Explanation of how the number of participants for analysis was determined.
Includes whether analysis was per protocol, intention to treat, or another method.
Also provides relevant details such as imputation technique, as appropriate.

PK Population. Only participants who were available at the indicated timepoints were analyzed.

Reporting Groups

Description

Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg

Participants received dabrefinib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.

Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg

Participants received dabrefinib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.

Number of Participants With the Best Overall Response as Assessed by the Investigator in Participants in Part D [ Time Frame: From the date of first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 280 days ) ]

Duration of Response as Assessed by the Investigator in Part D [ Time Frame: First documented evidence of PR or CR until the earlier of date of disease progression or date of death due to any cause (up to approximately 13 months) ]

Progression-free Survival (PFS) as Assessed by the Investigator in Part D [ Time Frame: From the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 13 months) ]

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts
the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release
and can embargo communications regarding trial results for a period that is less than or equal to 60 days.
The sponsor cannot require changes to the communication and cannot extend the embargo.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release
and can embargo communications regarding trial results for a period that is more than 60 days but less than
or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.

Restriction Description:
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.